Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test

Abstract

Recent studies revealed a causal link between ventral tegmental area (VTA) phasic dopamine (DA) activity and pro-depressive and antidepressant-like behavioral responses in rodent models of depression. Cholinergic activity in the VTA has been demonstrated to regulate phasic DA activity, but the role of VTA cholinergic mechanisms in depression-related behavior is unclear. The goal of this study was to determine whether pharmacological manipulation of VTA cholinergic activity altered behavioral responding in the forced swim test (FST) in rats. Here, male Sprague-Dawley rats received systemic or VTA-specific administration of the acetylcholinesterase inhibitor, physostigmine (systemic; 0.06 or 0.125 mg/kg, intra-cranial; 1 or 2 μg/side), the muscarinic acetylcholine receptor (AChR) antagonist scopolamine (2.4 or 24 μg/side), or the nicotinic AChR antagonist mecamylamine (3 or 30 μg/side), prior to the FST test session. In control experiments, locomotor activity was also examined following systemic and intra-cranial administration of cholinergic drugs. Physostigmine administration, either systemically or directly into the VTA, significantly increased immobility time in FST, whereas physostigmine infusion into a dorsal control site did not alter immobility time. In contrast, VTA infusion of either scopolamine or mecamylamine decreased immobility time, consistent with an antidepressant-like effect. Finally, the VTA physostigmine-induced increase in immobility was blocked by co-administration with scopolamine, but unaltered by co-administration with mecamylamine. These data show that enhancing VTA cholinergic tone and blocking VTA AChRs has opposing effects in FST. Together, the findings provide evidence for a role of VTA cholinergic mechanisms in behavioral responses in FST.

Muscarinic, but not nicotinic, acetylcholine receptor blockade in the ventral tegmental area attenuates cue-induced sucrose-seeking

“…These findings suggest that VTA mAChRs facilitate, but are not necessary for, cue-induced sucrose-seeking. Importantly, these Scop findings are not likely due to nonspecific motor effects, as we have previously demonstrated that VTA infusion of 24 μg Scop does not alter general locomotor activity [16]. Previous work also demonstrated that VTA Scop infusion does not alter operant responding in a progressive ratio task in rats that have already undergone operant acquisition training [13].…”

“…Drug doses were selected based on our previous investigations demonstrating the ability of these doses to alter phasic DA release and behavior [6, 15]. Importantly, we previously showed that VTA infusion of 24 μg Scop, 30 μg Mec, or 1 μg AP-5 did not alter locomotor activity [6, 16]. …”

Ventral tegmental area muscarinic receptors modulate depression and anxiety-related behaviors in rats

“…After the 1 min drug infusion, the internal cannulae were left in place for an additional 1 min to allow for complete diffusion of drug into the brain tissue. Physostigmine (0, 1, or 2 μg, VWR, Bridgeport, NJ), an acetylcholinesterase inhibitor, and pilocarpine (0, 3, or 30 μg, Sigma Aldrich, St. Louis, MO), a selective mAChR agonist, were each dissolved in 0.9% saline and infused at behaviorally relevant doses that we and others have previously used in the VTA [2, 21, 42]. VTA infusion of vehicle or drug was performed immediately prior to the sucrose preference, elevated plus maze, forced swim or locomotor test session.…”

“…Indeed, findings from our laboratory and others have shown that VTA cholinergic mechanisms regulate both phasic DA cell firing and downstream phasic DA release in the NAc [14, 22, 38]. Furthermore, our recent findings revealed a novel role for cholinergic activity in the VTA in mediating both pro-depressive and antidepressant-like behavioral responses in the forced swim test (FST) [2]. However, it is unclear whether VTA cholinergic mechanisms also regulate other behavioral phenotypes associated with depression and anxiety.…”

“…In the current study, our objective was to determine whether increasing cholinergic tone in the VTA of Sprague-Dawley rats would alter stress, anxiety, and anhedonia-related behaviors as measured in the FST, elevated plus maze (EPM), and sucrose preference test (SPT). Given our previous results showing the ability of muscarinic acetylcholine receptor (mAChR) blockade to reverse the pro-depressive effects of enhanced VTA cholinergic activity in the FST [2], we also examined whether direct VTA mAChR activation was sufficient to alter behavioral responses in the FST and EPM. Together, our findings provide novel insight into the role of VTA cholinergic, and specifically mAChR-mediated, mechanisms in response to stress and anxiety.…”